Aralkylamino substituted azacyclic therapeutic agents

ABSTRACT

Aralkylamino substituted azacyclic compounds of formula (I) and their salts and prodrugs. The variables are defined herein. The compounds are useful as tachykinin antagonists and are of particular use in the treatment of pain, inflammation, migraine, and emesis. ##STR1##

This application is a 371 of PCT/GB95/00153, Jan. 26, 1995.

This invention relates to a class of azacyclic compounds, which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention comprise an azacyclic ring system substituted by anaralkylamino moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and NK₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510!, specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis Levine et al Science (1984) 226,547-549!. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in"Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)! and emesis F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6!. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10!. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositisO'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8!. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions Hamelet et al, Can. J. Pharmacol. Physiol. (1988)66, 1361-7!, immunoregulation Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9! vasodilation,bronchospasm, reflex or neuronal control of the viscera Mantyh et al,PNAS (1988) 85, 3235-9! and, possibly by arresting or slowingβ-amyloid-mediated neurodegenerative changes Yankner et al, Science(1990) 250, 279-82! in senile dementia of the Alzheimer type,Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) Langdon et al,Cancer Research (1992) 52, 4554-7!.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis J. Luber-Narod etal, poster C.I.N.P. XVIIIth Congress, 28th Jun.-2nd Jul. 1992!, and indisorders of bladder function such as bladder detrusor hyper-reflexia(Lancet, 16th May 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic agents. It is for this reasonthat non-peptide tachykinin antagonists are sought.

In essence, this invention provides a class of potent non-peptidetachykinin antagonists. By virtue of their non-peptide nature, thecompounds of the present invention do not suffer from the shortcomings,in terms of metabolic instability, of the known peptide-based tachykininantagonists discussed above.

The present invention provides a compound of formula (I), or apharmaceutically acceptable salt or prodrug thereof: ##STR2## wherein

n is 1, 2 or 3 and where any carbon atom of (CH₂)_(n) may be substitutedby R⁴ and/or R5;

R¹ represents (CH₂)_(q) phenyl, wherein q is zero, 1, 2 or 3, which maybe optionally substituted in the phenyl ring by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b),--COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b) ;

R² represents aryl selected from phenyl and naphthyl; heteroarylselected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyland quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroarylmoiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

R³ represents H or C₁₋₆ alkyl;

R⁴ and R⁵ each independently represent H, halo, C₁₋₆ alkyl, oxo, CO₂R^(a) or CONR^(a) R^(b) ;

R⁶ represents H or C₁₋₆ alkyl;

R⁷ represents H, C₁₋₆ alkyl optionally substituted by a hydroxy group,or (CH₂)_(p) NR⁹ R¹⁰, CO₂ R¹⁶, CONR⁹ R¹⁰, (CH₂)_(p) CO₂ R¹⁶, (CH₂)_(p)CONR⁹ R₁₀, (CH₂)_(p) NR⁹ COR¹⁶, (CH₂)_(p) NHSO₂ R¹¹, (CH₂)_(p) OR¹⁶,(CH₂)_(p) OC(O)R⁹, (CH₂)_(p) OC₁₋₄ alkylCOR¹⁷, or phenyl optionallysubstituted by 1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,--OR^(a), --SR^(a), --SOR^(a), --SO₂ R^(a), --NR^(a) R^(b), --NR^(a)COR^(b), --NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b);

R⁸ represents H, COR^(a), CO₂ R^(a), COCONR^(a) R^(b), COCO₂ R^(a), C₁₋₆alkyl optionally substituted by a group selected from (CO₂ R^(a),CONR^(a) R^(b), hydroxy, cyano, COR^(a), NR^(a) R^(b), C(NOH)NR^(a)R^(b), CONHphenyl(C₁₋₄ alkyl), COCO₂ R^(a), CONHNR^(a) R^(b), C(S)NR^(a)R^(b), CONR^(a) C₁₋₆ alkylR¹², CONR¹³ C₂₋₆ alkynyl, CONR¹³ C₂₋₆ alkenyl,COCONR^(a) R^(b), CONR^(a) C(NR^(b))NR^(a) R^(b), CONR^(a) heteroaryl,and phenyl optionally substituted by one or more substituents selectedfrom C₁₋₆ alkyl, C₁₋₆ alkoxy, halo and trifluoromethyl) or C₁₋₆ alkyl,optionally substituted by oxo, substituted by an optionally substitutedaromatic heterocycle;

with the proviso that when R⁶ and R⁷ both represent H, R⁸ representsC₁₋₆ alkyl optionally substituted by oxo, substituted by an optionallysubstituted aromatic heterocycle selected from pyrrolyl, pyrazolyl,pyrazinyl, pyridazinyl, oxadiazolyl, thiadiazolyl, imidazolyl,benzimidazolyl, benzoxazolyl, benzthiophenyl, benzofuranyl and indolyl,or a substituted aromatic heterocycle selected from thienyl, furyl,pyridyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, quinolyl,isoxazolyl and isothiazolyl;

R^(a) and R^(b) each independently represent H, C₁₋₆ alkyl,trifluoromethyl or phenyl optionally substituted by C₁₋₆ alkyl, halo ortrifluoromethyl;

R⁹ and R¹⁰ each independently represent H or C₁₋₆ alkyl;

R¹¹ represents NR¹⁴ R¹⁵ or an optionally substituted aromatic ornon-aromatic azacyclic or azabicyclic group;

R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl;

R¹³ represents H or C₁₋₆ alkyl;

R¹⁴ and R¹⁵ each independently represent H, C₁₋₆ alkyl, phenyloptionally substituted by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, haloor trifluoromethyl, or phenylC₁₋₄ alkyl optionally substituted in thephenyl ring by one or more of C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

R¹⁶ represents C₁₋₆ alkyl;

R¹⁷ represents C₁₋₆ alkoxy, amino, C₁₋₄ alkylamino or di(C₁₋₄alkyl)amino; and

p is 1 to 4.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to theabove formula may represent straight, branched or cyclic groups. Thus,for example, suitable alkyl groups include methyl, ethyl, n- oriso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such ascyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; andsuitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chloro, bromo and iodo,especially chloro and fluoro.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. In particular, the relative orientation of the 2-and 3- substituents on the azacyclic ring may give rise to cis and transdiastereoisomers, of which the cis stereochemistry is preferred. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Preferably n is 2 or 3, more preferably 3.

Preferably q is zero and R¹ represents substituted phenyl. When R¹ issubstituted phenyl suitable substituents include nitro, trifluoromethyl,trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl,cyclopropyl, vinyl, methoxy, phenoxy, amino and carbonylmethoxy.Preferably R¹ represents phenyl substituted by one or more groupsselected from methyl, trifluoromethyl, chloro and t-butyl.

Preferably R¹ represents disubstituted phenyl, more preferably3,5-disubstituted phenyl such as 3,5-dichlorophenyl or3,5-bis(trifluoromethyl)phenyl, or monosubstituted phenyl, such as3-substituted phenyl, e.g. 3-t-butylphenyl.

Preferably R² represents unsubstituted benzhydryl, phenyl substituted byhalo such as fluoro, for example 4-fluorophenyl, or unsubstitutedphenyl, more preferably unsubstituted phenyl.

Preferably R⁴ and R⁵ both represent H.

Suitable values for R⁶ include H, methyl and ethyl. Preferably R⁶represents H or methyl, more preferably H.

Preferably R⁷ represents C₁₋₆ alkyl optionally substituted by a hydroxygroup, such as methyl, ethyl, CH₂ OH, CH₂ CH₂ OH, CH(OH)CH₃ orC(OH)(CH₃)₂, more preferably methyl or CH₂ OH.

When R⁸ represents C₁₋₆ alkyl, optionally substituted by oxo,substituted by a substituted aromatic heterocycle, suitable substituentsin the heterocyclic ring include C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, thioxo,halo, trifluoromethyl, NR^(a) R^(b), NR^(a) COR^(b), CONR^(a) R^(b), CO₂R^(a), SO₂ R^(a) and CH₂ OR^(a), where R^(a) and R^(b) are as previouslydefined.

Preferably R⁸ represents C₁₋₃ alkyl such as methyl, ethyl or i-propylsubstituted by a substituted or unsubstituted aromatic heterocycle.Suitable heterocycles include thienyl, furyl, pyrrolyl, pyridyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl,oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl,imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyland indolyl.

In one group of compounds according to the invention R⁸ represents CH₂-Het, CH(CH₃)-Het, C(CH₃)₂ -Het or C(O)-Het, where Het is pyrrolyl,pyrazolyl, pyrazinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranylor indolyl.

Preferably R⁸ represents CH₂ -Het, CH(CH₃)-Het, C(CH₃)₂ -Het or C(O)-Hetwhere Het is substituted or unsubstituted oxazolyl, oxadiazolyl,tetrazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, triazolyl,pyrazinyl, pyridyl, pyridazinyl, imidazolyl or benzimidazolyl. Morepreferably Het is triazolyl or triazolyl substituted by oxo.

Other suitable values for R⁸ include H, COR^(a), CO₂ R^(a), COCONR^(a)R^(b), COCO₂ R^(a), C₁₋₆ alkyl and C₁₋₆ alkyl substituted by a groupselected from CO₂ R^(a), CONR^(a) R^(b), CN, C(NOH)NR^(a) R^(b),CONHphenyl(C₁₋₄ alkyl), optionally substituted phenyl, CONHNR^(a) R^(b),COCONR^(a) R^(b), CONR^(a) C(NH)NH₂, CSNR^(a) R^(b), CONR¹³ C₂₋₆alkynyl, CONR^(a) C₁₋₆ alkylR¹² and CONR^(a) heteroaryl.

It will be appreciated that, when R⁸ comprises a heteroaryl moietysubstituted by an oxo or thioxo substituent, different tautomeric formsare possible so that the substituent on the heteroaryl moiety may berepresented as ═O or --OH, or ═S or --SH, respectively. For theavoidance of doubt, all such tautomeric forms are embraced by thepresent invention.

When R¹¹ represents NR¹⁴ R¹⁵, R¹⁴ and R¹⁵ are preferably both C₁₋₆ alkylsuch as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.More preferably R¹⁴ and R¹⁵ will both represent methyl.

When R¹¹ represents an aromatic or non-aromatic azacycle or azabicycleit may contain one or more additional heteroatoms selected from O, S andN or groups NR¹⁸, where R¹⁸ is H, C₁₋₆ alkyl or phenylC₁₋₄ alkyl, andmay be unsubstituted or substituted. Suitable substituents include C₁₋₆alkyl, C₁₋₆ alkoxy, oxo, SH, ═S, halo, trifluoromethyl, NR^(a) R^(b),NR^(a) COR^(b), CONR^(a) R^(b), CO₂ R^(a) and CH₂ OR^(a), where R^(a)and R^(b) are as previously defined.

When R¹¹ represents an aromatic azacycle or azabicycle, suitable valuesof R¹¹ include imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl,pyrrolyl, pyrazolyl, pyrazinyl, pyridyl, oxadiazolyl, thiadiazolyl,isoxazolyl, isothiazolyl, benzimidazolyl, benzoxazolyl and indolyl,preferably imidazolyl, such as 2,4-imidazolyl, or pyridyl, morepreferably pyridyl such as 4-, 3- or 2-pyridyl.

When R¹¹ represents a non-aromatic azacycle or azabicycle, suitablevalues of R¹¹ include morpholinyl, piperdinyl, pyrrolidinyl,piperazinyl, methylpiperazinyl, azanorbornanyl, azabicyclo 2.2.2!octanyland azabicyclo 3.2.2!nonyl, preferably morpholinyl, pyrrolidinyl,methylpiperazinyl, quinuclidinyl (azabicyclo 2.2.2!octanyl) orazabicyclo 3.2.2!nonyl, more preferably pyrrolidinyl.

A particular sub-class of compounds according to the present inventionis represented by compounds of formula (Ia), and pharmaceuticallyacceptable salts and prodrugs thereof: ##STR3## wherein

R¹, R², R³, R⁴, R⁵, R⁶, R⁸ and n are as defined for formula (I) above;and

R⁷ represents C₁₋₆ alkyl optionally substituted by a hydroxy group, or(CH₂)_(p) NR⁹ R¹⁰, CO₂ R¹⁶, CONR⁹ R¹⁰, (CH₂)_(p) CO₂ R¹⁶, (CH₂)_(p)CONR⁹ R¹⁰, (CH₂)_(p) NR⁹ COR¹⁶, (CH₂)_(p) NHSO₂ R¹¹, (CH₂)_(p) OR¹⁶,(CH₂)_(p) OC(O)R⁹, (CH₂)_(p) OC₁₋₄ alkylCOR¹⁷, or phenyl optionallysubstituted by 1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl,--OR^(a), --SR^(a), --SOR^(a), --SO₂ R^(a), --NR^(a) R^(b), --NR^(a)COR^(b), --NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) and --CONR^(a)R^(b).

A preferred sub-class of compounds according to the present invention isrepresented by compounds of formula (Ib), and pharmaceuticallyacceptable salts and prodrugs thereof: ##STR4## wherein

R², R³, R⁴, R⁵, R⁶, R⁸ and n are as defined for formula (I) above;

R¹⁸ represents C₁₋₆ alkyl optionally substituted by a hydroxy group; and

R¹⁹ represents phenyl optionally substituted by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b),--COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b).

A further preferred sub-class of compounds according to the presentinvention is represented by compounds of formula (Ic) andpharmaceutically acceptable salts and prodrugs thereof: ##STR5## wherein

R³ and R⁸ are as defined for formula (I);

R²⁰ and R²¹ independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, chloro, bromo, fluoro, iodo, cyano, nitro, trifluoromethyl,trimethylsilyl, OR^(a), SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), whereR^(a) and R^(b) are as previously defined;

R²² is methyl optionally substituted by hydroxy;

R²³ is H or methyl; and

R²⁴ represents phenyl or benzhydryl wherein any of the phenyl rings ofthe phenyl or benzhydryl moieties may optionally be substituted by haloor trifluoromethyl, preferably unsubstituted phenyl.

Particular values of R²⁰ and R²¹ include methyl, ethyl, t-butyl, chloro,fluoro and trifluoromethyl. Preferably R²⁰ and R²¹ are both other thanhydrogen and are located at the 3- and 5-positions of the phenyl ring.

A preferred group of compounds according to the present invention arecompounds of formula (Ic) wherein R⁸ is optionally substitutedtriazolyl.

Another particular sub-class of compounds according to the presentinvention is represented by compounds of formula (Id), andpharmaceutically acceptable salts and prodrugs thereof: ##STR6## wherein

R¹, R², R³, R⁴, R⁵, and n are as defined for formula (I) above; and

R⁸ represents C₁₋₆ alkyl, optionally substituted by oxo, substituted byan optionally substituted aromatic heterocycle selected from pyrrolyl,pyrazolyl, pyrazinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,imidazolyl, benzimidazolyl, benzoxazolyl, benzthiophenyl, benzofuranyland indolyl, or a substituted aromatic heterocycle selected fromthienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,quinolyl, isoxazolyl and isothiazolyl.

Another particularly preferred sub-class of compounds according to thepresent invention is represented by compounds of formula (Ie), andpharmaceutically acceptable salts and prodrugs thereof: ##STR7## whereinR², R³, R⁴, R⁵, R⁸ and n are as defined for formula (Id) above; and

R¹⁹ represents phenyl optionally substituted by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b),--COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b).

A yet further preferred sub-class of compounds according to the presentinvention is represented by compounds of formula (If) andpharmaceutically acceptable salts and prodrugs thereof: ##STR8## wherein

R³ and R⁸ are as defined for formula (I);

R²⁰ and R²¹ independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, chloro, bromo, fluoro, iodo, cyano, nitro, trifluoromethyl,trimethylsilyl, OR^(a), SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), whereR^(a) and R^(b) are as previously defined; and

R²⁴ represents phenyl or benzhydryl wherein any of the phenyl rings ofthe phenyl or benzhydryl moieties may optionally be substituted by haloor trifluoromethyl, preferably unsubstituted phenyl.

Particular values of R²⁰ and R²¹ include methyl, ethyl, t-butyl, chloro,fluoro and trifluoromethyl. Preferably R²⁰ and R²¹ are both other thanhydrogen and are located at the 3- and 5-positions of the phenyl ring.

A preferred group of compounds according to the invention are compoundsof formula (If) wherein R⁸ is substituted triazolyl.

Specific compounds within the scope of the present invention include:

cis-3-((3,5-bis(trifluoromethyl))(α-methyl)benzylamino)-2-(4-fluorophenyl)piperidine;

cis-3-((3,5-bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidine-1-ylmethyl!-2,4-dihydro-1,2,4!-triazol-3-one;

and pharmaceutically acceptable salts and prodrugs thereof.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts (such as thedibenzoyltartrate salts) may, however, be useful in the preparation ofthe compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleicacid, succinic acid, acetic acid, citric acid, tartaric acid, carbonicacid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groupsmay also comprise quaternary ammonium salts in which the amino nitrogenatom carries a suitable organic group such as an alkyl, alkenyl, alkynylor aralkyl moiety. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include metal salts such as alkali metal salts, e.g. sodiumor potassium salts; and alkaline earth metal salts, e.g. calcium ormagnesium salts.

Preferred salts of the compounds according to the invention include thehydrochloride and p-toluenesulphonic acid salts.

The invention also provides pharmaceutical compositions comprising acompound of this invention in association with a pharmaceuticallyacceptable carrier. Preferably these compositions are in unit dosageforms such as tablets, pills, capsules, powders, granules, solutions orsuspensions, or suppositories, for oral, parenteral or rectaladministration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are adminsitered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; epilepsy; neurodegenerativedisorders such as dementia, including senile dementia of the Alzheimertype, Alzheimer's disease and Down's syndrome; demyelinating diseasessuch as MS and ALS and other neuropathological disorders such asperipheral neuropathy, for example diabetic and chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; small cell carcinomassuch as small cell lung cancer; respiratory diseases, particularly thoseassociated with excess mucus secretion such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, and bronchospasm; inflammatory diseases such as inflammatorybowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoidarthritis, pruritis and sunburn; allergies such as eczema and rhinitis;hypersensitivity disorders such as poison ivy; ophthalmic diseases suchas conjunctivitis, vernal conjunctivitis, and the like; ophthalmicconditions associated with cell proliferation such as proliferativevitreoretinopathy; cutaneous diseases such as contact dermatitis, atopicdermatitis, urticaria, and other eczematoid dermatitis; addictiondisorders such as alcoholism; stress related somatic disorders; reflexsympathetic dystrophy such as shoulder/hand syndrome; dysthymicdisorders; adverse immunological reactions such as rejection oftransplanted tissues and disorders related to immune enhancement orsuppression such as systemic lupus erythematosus; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera, ulcerative colitis, Crohn's disease,irritable bowel syndrome and emesis, including acute, delayed oranticipatory emesis such as emesis induced by chemotherapy, radiation,toxins, viral or bacterial infections, pregnancy, vestibular disorders,motion, surgery, migraine, and variations in intercranial pressure, inparticular, for example, drug or radiation induced emesis orpost-operative nausea and vomiting; disorders of bladder function suchas cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosingand collagen diseases such as scleroderma and eosinophilic fascioliasis;disorders of blood flow caused by vasodilation and vasospastic diseasessuch as angina, migraine and Reynaud's disease; and pain or nociception,for example, that attributable to or associated with any of theforegoing conditions, especially the transmission of pain in migraine.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed or anticipatory emesis, such as emesisinduced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, motion, surgery, migraine, and variations in intercranialpressure. Most especially, the compounds of formula (I) are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agentsincluding those routinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in Nausea and Vomiting: Recent Research andClinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton,Fla., USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil R. J. Gralla et al in Cancer TreatmentReports (1984)68(1), 163-172!.

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide. Additionally, acompound of formula (I) may be administered in combination with ananti-inflammatory corticosteroid, such as dexamethasone. Furthermore, acompound of formula (I) may be administered in combination with achemotherapeutic agent such as an alkylating agent, antimetabolite,mitotic inhibitor or cytotoxic antibiotic, as described above. Ingeneral, the currently available dosage forms of the known therapeuticagents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen 1 to 4 times per day, preferably once or twiceper day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 2 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

The compounds according to the present invention may be prepared by aprocess (A) which comprises reacting a compound of formula (II) with acompound of formula (III): ##STR9## wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸and n are as defined for formula (I), except that any reactive moiety isprotected by a suitable protecting group; and one of R³⁰ and R³¹represents a leaving group and the other of R³⁰ and R³¹ represents NHR³,where R³ is as defined for formula (I); in the presence of a base,followed by deprotection, if required.

Suitably R³⁰ represents NHR³ and R³¹ represents a leaving group.

Suitable leaving groups include halo, e.g. chloro, bromo or iodo, orsulphonate derivatives such as tosylate, mesylate or triflate.

The reaction is conveniently carried out in a suitable organic solvent,such as an ether, e.g. 1,2-dimethoxyethane, at a temperature in theregion of 0° C. Favoured bases of use in the reaction include alkalimetal amides and hydrides, such as potassium bis(trimethylsilyl)amide orpotassium hydride. Suitably, sodium hydride is used.

According to another process (B), compounds of formula (I) wherein R⁶ ishydrogen, may be prepared by the reductive amination of a compound offormula (II) in which R³⁰ is the group NHR³, with a compound of formulaR¹ COR⁷, in the presence of a reducing agent. Suitable reducing agentsfor use in this reaction include, for example, sodium cyanoborohydrideor sodium triacetoxyborohydride, or catalytic hydrogenation. Thereaction is conveniently effected in a suitable solvent such as aceticacid or methanol at a temperature between 0° C. and 50° C., convenientlyat about room temperature.

Alternatively, according to a further process (C), compounds of formula(I) may be prepared from different compounds of formula (I) byinterconversion processes. In particular, interconversion processes maybe used to vary the group R⁸. For example, compounds of formula (I)wherein R⁸ is other than H may be prepared from the correspondingcompounds of formula (I) wherein R⁸ is H by reaction with a reagentsuitable to introduce the group R⁸, for example, a halide or acylhalide, or corresponding mesylate or tosylate, of formula R⁸ -L, where Lrepresents halo, such as chloro, bromo or iodo, methylsulphonate or p-toluenesulphonate, or any other suitable leaving group, in the presenceof a base. Suitable bases of use in the reaction include inorganic basessuch as alkali metal carbonates, for example, potassium carbonate.Conveniently the reaction is effected in a suitable organic solvent, forexample, dimethylformamide.

Compounds of formula (I) wherein R⁸ is COR^(a) may be prepared fromcompounds of formula (I) wherein R⁸ is H by, for example, reaction withan appropriate acid anhydride.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl may be prepared fromcorresponding compounds of formula (I) wherein R⁸ is COR^(a) byreduction using, for example, borane or a borohydride such as sodiumcyanoborohydride.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted byCONR^(a) R^(b) may be prepared from corresponding compounds of formula(I) wherein R⁸ is C₁₋₆ alkyl substituted by CO₂ R^(a) by treatment withammonia or an amine of formula NR^(a) R^(b).

Compounds of formula (I)wherein R⁸ is C₁₋₆ alkyl substituted by5-oxadiazolyl may be prepared from compounds of formula (I) wherein R⁸is C₁₋₆ alkyl substituted by CO₂ R^(a), where R^(a) represents C₁₋₆alkyl, by reaction with a compound of formula (IV) ##STR10## wherein R³²represents H or a suitable substituent, in the presence of a base.

Suitable bases of use in the reaction include alkali metals, such as,for example, sodium, and alkali metal hydrides, such as, for example,sodium hydride.

The reaction is conveniently effected in a suitable organic solvent.Which solvents will be appropriate will depend on the nature of the baseused. For example, where the base used is an alkali metal, suitablesolvents will include alcohols, for example, ethanol, whereas where thebase used is an alkali hydride, suitable solvents will include ethers,for example, tetrahydrofuran.

Preferably the reaction is conducted at elevated temperature, such asthe reflux temperature of the chosen solvent.

Compounds of formula (I)wherein R⁸ is C₁₋₆ alkyl substituted bytetrazolyl may be prepared from compounds of formula (I) wherein R⁸ isC₁₋₆ alkyl substituted by cyano by treatment with an alkali metal azide,such as sodium azide.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted bythiazolyl may be prepared from compounds of formula (I) wherein R⁸ isC₁₋₆ alkyl substituted by CSNH₂ by reaction with a compound of formulaHal-CH₂ C(O)--R⁶⁰, where Hal is halo, such as bromo, chloro or iodo, andR⁶⁰ represents H or a suitable substituent.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted bythioxotriazolyl may be prepared from compounds of formula (I) wherein R⁸is C₁₋₆ alkyl substituted by CONHNH₂ by reaction with a compound offormula R⁶¹ NCS, wherein R⁶¹ represents H or a suitable substituent suchas C₁₋₆ alkyl, in the presence of a base.

Suitable bases of use in the reaction include organic bases such as, forexample, 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU). The reaction isconveniently effected in a suitable organic solvent, such as alcohol,e.g. butanol.

Compounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted byunsubstituted or substituted triazolyl may be prepared from compounds offormula (V) ##STR11## wherein Hal is as previously defined, m is 1, 2,3, 4, 5 or 6 and R⁶² is H or a group suitable as a substituent of thetriazole ring, or convertable to such a group under the reactionconditions, in the presence of a base.

Suitable bases of use in the reaction include alkali metal carbonates,such as, for example, potassium carbonate.

Suitably R⁶² represents H, OCH₃ (which is converted to an oxosubstituent under the reaction conditions) or CONH₂.

The reaction is conveniently effected in an anhydrous organic solvent,such as, for example, anhydrous dimethylformamide, preferably atelevated temperature, such as about 60° C.

Compounds of formula (I) wherein R⁸ represents C₁₋₆ alkyl substituted byCONR^(a) C₁₋₆ alkylR¹² or CONR^(a) heteroaryl may be prepared fromcompounds of formula (I) wherein R⁸ is C₁₋₆ alkyl substituted by CO₂ Hby reaction with an amine of formula HNR^(a) C₁₋₆ alkylR¹² or HNR^(a)heteroaryl.

Alternatively, compounds of formula (I) in which R⁷ represents, inparticular, CO₂ R¹⁶ may be converted into other compounds of formula(I). Thus compounds of formula (I) where R⁷ is CO₂ R¹⁶ may be reactedwith a Grignard reagent of formula R^(c) MgHal where R^(c) is an alkylgroup and Hal is as previously defined to give compounds where R⁷ is atertiary alcohol. Secondary alcohols may be prepared firstly byreduction of the ester moiety to an aldehyde using, for example,diisobutylaluminium hydride, followed by reaction with either R^(c) Lior R^(c) MgHal.

The aldehyde may also be used as a precursor for alkenyl intermediateswhere the group at position R⁷ has the formula --CH═CHR^(d), where R^(d)is (CH₂)_(s) NR⁹ R¹⁰, (CH₂)_(s) CO₂ R¹⁶, (CH₂)_(s) CONR⁹ R¹⁰ or(CH₂)_(s) NR⁹ COR¹⁶ (where s is 0, 1 or 2 and R⁹, R¹⁰ and R¹⁶ are aspreviously defined). These compounds may be prepared by a Wittigreaction using, for example, Ph₃ P═CHR^(d) or (EtO)₃ P(O)═CHR^(d). Thesealkenyl intermediates may be reduced using, for example, catalytichydrogenation to give compounds wherein R⁷ is (CH₂)_(p) NR⁹ R¹⁰,(CH₂)_(p) CO₂ R¹⁶, (CH₂)_(p) CONR⁹ R¹⁰ or (CH₂)_(p) NR⁹ COR¹⁶ and p is 2to 4.

Compounds wherein R⁷ is CONR⁹ R¹⁰ may be prepared by the reaction of acompound of formula (I) wherein R⁷ is CO₂ R¹⁶, and R¹⁶ is methyl, withan amine of the formula HNR⁹ R¹⁰ by known methods. Subsequent reductionusing, for example, borane in tetrahydrofuran may be used to give acompound wherein R⁷ is (CH₂)_(p) NR⁹ R¹⁰ in which p is 1. Where one orboth of R⁹ and R¹⁰ in the resultant amine is a hydrogen atom, the aminemay be further converted into a compound wherein R⁷ is (CH₂)_(p) NR⁹COR¹⁶ by reaction with, for example, an acyl chloride of the formula R¹⁶COCl by known methods.

Compounds wherein R⁷ is CH₂ OH may be prepared by the reduction of acompound of formula (I) wherein R⁷ is CO₂ R¹⁶, and R¹⁶ is methyl, using,for example, lithium aluminium hydride. The primary alcohol may be usedto prepare a compound of formula (I) wherein R⁷ is (CH₂)_(p) OR¹⁶ and pis 1 by reaction with a halide of the formula R¹⁶ Hal, where Hal is aspreviously defined in the presence of a suitable base such as sodiumhydride.

If a compound of the formula (I) is required in which R⁶ is an alkylgroup it may be prepared via a corresponding compound of the formula (I)in which R⁷ is CO₂ R¹⁶ group by reaction with KHMDS and an alkyl iodide,followed, if desired, by conversion of the CO₂ R¹⁶ group as describedabove.

According to a further general process (D), compounds of formula (I)wherein R⁸ represents H and n is 2 or 3 may be prepared from a compoundof formula (VI) ##STR12## wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are asdefined for formula (I) and x is 1 or 2 by reduction. Suitable reducingagents will be readily apparent to one skilled in the art and include,for example, borane or metallic hydrides, such as lithium aluminiumhydride or sodium borohydride. Borane is preferred.

Compounds of formula (VI) wherein R⁶ is C₁₋₆ alkyl and R⁷ is H may beprepared by reductive amination of a compound of formula (VII) ##STR13##wherein R², R³, R⁴, and R⁵ are as defined for formula (I) except thatany reactive moiety is protected by a suitable protecting group and x is1 or 2, using, for example, sodium cyanoborohydride or sodiumtriacetoxyborohydride and a compound of the formula R¹ COR⁶ where R⁶ isC₁₋₆ alkyl. The reaction is generally effected in a polar solvent suchas acetic acid or methanol at a temperature between 0° and 50° C.,conveniently at room temperature.

Alternatively, compounds of formula (VI) may be prepared by the reactionof a compound of formula (VII) with a compound of formula (Ill) in whichR³¹ is a leaving group such as a halogen atom, for example, a bromineatom. The reaction is effected in the presence of a base, for example,potassium carbonate and in a suitable solvent such as dimethylformamide.

It will be appreciated that the product of the reductive aminationmethod described herein will be a mixture of stereoisomers at theposition of the group R⁶. For the subsequent preparation of a specificisomer of a compound of formula (I) wherein R⁶ is C₁₋₆ alkyl and R⁷ isH, the mixture of stereoisomers may be resolved by conventional methods,for example, by column chromatography.

Methods for the preparation of intermediates of formula (VII) andformula (II) when R³⁰ is NHR³ are described, for example, in EuropeanPatent Specification No. 0 436 334.

Where they are not commercially available, the intermediates of formula(III) above may be prepared by the procedures described in theaccompanying Examples or by alternative procedures which will be readilyapparent to one skilled in the art.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. For example, compounds which contain a hydroxy group may beresolved into their component enantiomers by standard techniques, suchas the formation of diastereomeric esters or amides, followed bychromatographic separation or separation by fractional crystallizationand removal of the chiral auxiliary. Where they are intermediates,diastereomeric alcohols can then be used to prepare optically purecompounds of formula (I).

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC₅₀ at the NK1receptor of less than 150 nM.

The compounds of this invention may be formulated as specificallyillustrated at pages 35 to 36 of International Patent Specification No.WO 93/01165.

The following Examples illustrate the preparation of compounds accordingto the invention.

Intermediate 1

cis-5-((3,5-Bis(trifluoromethyl))(α-methyl)benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine(isomers A and B)

5-Amino-6-(4-fluorophenyl)-2-oxo-piperidine (1.7 g), citric acid (0.8 g)and bis(trifluoromethyl)acetophenone (2.3 g) were dissolved in methanol(30 ml), powdered 4 Å molecular sieves (2 g) were added. After stirringfor 5 minutes sodium cyanoborohydride (0.56 g) was added, after stirringfor a further 60 minutes the mixture was evaporated to dryness. Theresidue was suspended in dichloromethane (30 ml) and filtered throughcelite, the filtrate was then washed with 5% aqueous sodium bicarbonate(20 ml), then dried (MgSO₄) and the solvent evaporated. The residue waspurified by chromatography on silica (ethyl acetate:methanol, 9:1 ), toafford (isomer A)cis-5-((3,5-bis(trifluoromethyl))(α-methyl)benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine(0.52 g) mp 138° C., and, (isomer B)cis-5-((3,5-bis(trifluoromethyl))(α-methyl)benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine(0.21 g) mp 120° C.

Intermediate 2

cis-5-((3,5-Bis(trifluoromethyl))benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine

5-Amino-6-(4-fluorophenyl)-2-oxo-piperidine (1 g), citric acid (0.5 g)and bis(trifluoromethyl)benzaldehyde (1.3 g) were dissolved in methanol(20 ml), powdered 4 Å molecular sieves (2 g) were added. After stirringfor 5 minutes sodium cyanoborohydride (0.34 g) was added, after stirringfor a further 60 minutes the mixture was evaporated to dryness. Theresidue was suspended in dichloromethane (30 ml) and filtered throughcelite, the filtrate was then washed with 5% aqueous sodium bicarbonate(20 ml), then dried (MgSO₄) and the solvent evaporated. The residue waspurified by chromatography on silica (ethyl acetate:methanol, 9:1), toaffordcis-5-((3,5-bis(trifluoromethyl))benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine(1.1 g)

¹ H NMR 1.64-1.72 (1H,m), 2.13-2.49 (3H,m), 2.95 (1H,br s), 377-3.86(2H,m), 4.66 (1H,br s), 7.14 (2H,t,J=6 Hz), 7.28(2H,t,J=6 Hz), 7.76(1H,s), 7.82 (2H,s), 7.88 (1H,s).

Intermediate 3

cis-3-((3,5-Bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidine

cis-5-((3,5-Bis(trifluoromethyl))benzylamino)-6-(4-fluorophenyl)-2-oxo-piperidine(1 g) was dissolved in tetrahydrofuran (15 ml), a solution of borane inTHF was added dropwise (4.4 ml of 1M solution), the resulting solutionwas then heated at reflux for 2 hours. The mixture was then cooled toroom temperature and methanol (5 ml) added dropwise, the resultingmixture was evaporated to dryness. The residue was dissolved in ethanol(20 ml) potassium carbonate (1 g) added and the mixture heated at refuxfor 4 hours. The mixture was then evaporated to dryness and the residueextracted with hot dichloromethane (2×20 ml), ethereal HCl was added tothe extracts and the product isolated by filtration. Recrystallisationfrom ethano/ether affordedcis-3-((3,5-bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidineas a dihydrochloride salt m.p. 290° C.

EXAMPLE 1

cis-3-((3,5-Bis(trifluoromethyl)(α-methyl)benzylamino)-2-(4-fluorophenyl)piperidine(Isomer B)

Cis-5-((3,5-Bis(trifluoromethyl))(α-methyl)benzylamino)6-(4-fluorophenyl)-2-oxo-piperidine(isomer B) (0.2 g) was dissolved in tetrahydrofuran (15 ml), a solutionof borane in THF was added dropwise (2 ml of 1M soln), the resultingsolution was then heated at reflux for 2 hours. The mixture was thencooled to room temperature and methanol (5 ml) added dropwise, theresulting mixture was evaporated to dryness. The residue was dissolvedin ethanol (20 ml) potassium carbonate (1 g) added and the mixtureheated at refux for 4 hours. The mixture was then evaporated to drynessand the residue extracted with hot dichloromethane (2×20 ml), etherealHCl was added to the extracts and the product isolated by filtration.Recrystallisation from ethanol/ether affordedcis-3-((3,5-bis(trifluoromethyl))(α-methyl)benzylamino)-2-(4-fluorophenyl)piperidine(Isomer B) as a dihydrochloride salt. m.p. 235° C.

EXAMPLE 2

cis-5-3-((3,5-Bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidin-1-ylmethyl!-2,4-dihydro-1,2,4!-triazol-3-one

cis-3-((3,5-Bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidinedihydrochloride salt (0.68 g) was partitioned between chloroform (50 ml)and 10% aqueous potassium bicarbonate (20 ml), the organic phase wasseparated, dried (Na₂ SO₄) and evaporated to afford the free base (0.5g). The free base was dissolved in DMF (19 ml) and K₂ CO₃ (0.8 g),N-carbomethoxy-2-chloroacetamidrazone (0.2 g) was added and the mixtureheated to 60° C. for 30 minutes. The mixture was then heated to 140° C.for a further 2 hours, cooled to room temperature and the solventremoved at reduced pressure. The residue was purified by chromatography(ethyl acetate:methanol, 9:1), the oil isolated was dissolved indichloromethane and treated with ethereal HCl to afford thedihydrochloride salt, mp 225° C.

EXAMPLE 3

cis-(±)-3-(2-Hydroxy-1-(4-fluorophenyl)ethylamino)-2-phenylpiperidine

a) To a methanol (5 ml) solution of (±) 5-amino-6-phenylpiperidin-2-one(1.67 g, cis:trans isomers (6:1)) was added a solution oftoluene-4-sulphonic acid monohydrate (1.8 g) in methanol (5 ml). Thesolid which formed by crystallization was removed by filtration to givepure cis isomer; mp 242°-244° C. A sample of this material (0.9 g) wasdissolved in warm water (10 ml) and this solution was applied to acolumn containing Dowex™ 50W-X8 (H⁺ form, 20 ml). After washing thecolumn with water the product was eluted with dilute aqueous ammonia(2M) and the fractions containing product were evaporated to dryness. Toa solution of the residue (0.32 g) in dimethylformamide (5 ml) was addedK₂ CO₃ (0.7 g) and 2-bromo-2-(4-fluorophenyl)acetic acid (0.42 g). Afterstirring at room temperature for 16h, water (20 ml) and ethyl acetate(20 ml) were added and the organic phase washed with water, saturated inbrine and dried (MgSO₄). The solvent was removed in vacuo and theresidue purified on silica gel eluting with ethyl acetate to give, as a0.7:1 mixture of diastereomers, methylcis(±)5-(N-(4-fluorophenylglycinate))-6-phenylpiperidin-2-one. ¹ H NMR(250 MHz, CDCl₃) δ7.45-7.09 (9H,m), 5.97 (0.4H,br d), 5.77 (br s), 4.90(m), 4.78 (d, J=3.6 Hz), 4.68 (d, J=3.5 Hz), 4.6 (m), 4.05 (s+s), 3.61(s, OMe), 3.54 (s, OMe), 3.08 (m), 2.87 (m), 2.75-2.3 (m), 1.90 (m). MSm/z (Cl⁺) 357 (M+H).

b) A solution of the diastereomeric mixture (Example 3a, 0.32 g) intetrahydrofuran (4 ml) was added to a solution of lithium aluminiumhydride (1M in tetrahydrofuran, 2 ml). The solution was stirred at roomtemperature for 15 minutes then at 40° C. for 1 hour. Water (20 ml) wasadded carefully to the solution followed by ethyl acetate (20 ml). Theorganic phase was washed with saturated brine and dried (MgSO₄). Theresidue after evaporation was chromatographed on silica gel eluting witha gradient between CH₂ Cl₂ and methanol, CH₂ Cl₂, aqueous ammonia(10:90:0.4) to give after crystallization from diethylether:

diastereomer A: mp=157°-159° C., ¹ H NMR (250 MHz, CDCl₃) δ7.33-7.18(5H, m, phenyl), 6.7 (dd, 2H, J=8.72 Hz), 6.51 (2H, dd, J=8.64 Hz, 5.44Hz, aryl), 3.89 (1H, d, J=2.4 Hz, NHCHPh), 3.5 (2H, m), 3.22 (2H, m),3.00 (1H, vbr s), 2.80 (1H, td, J=12.01, 2.75 Hz), 2.70 (1H, d, J=2.49Hz), 1.90 (2H, m), 1.54 (2H, m) m/z (Cl⁺) 315 (M+H); and

diastereomer B: mp=116°-120° C., ¹ H NMR (250 MHz, CDCl₃) δ7.38-7.25(5H, m), 7.0 (2H, dd, J=6.6, 8.7 Hz), 6.74 (2H, dd, J=8.7, 8.7 Hz), 3.8(1H, d, J=2.3 Hz), 3.28 (1H, dd, J=10.6, 4.5 Hz), 3.18 (2H, m), 3.04(1H, m), 2.78 (2H, m), 1.60 (3H, m), 1.37 (1H, m) m/z (Cl⁺) 315 (M+H).

EXAMPLE 4

cis-(±)-3-(2-Hydroxy-1-phenylethylamino)-phenylpiperidine

The title compound was prepared in an analogous manner to that describedin Example 3 using (±) 5-amino-6-phenylpiperidin-2-one and2-bromo-2-phenylacetic acid as starting materials. MS m/z (Cl⁺) 297(M+H).

We claim:
 1. A compound of formula (I), or a pharmaceutically acceptablesalt: ##STR14## wherein n is 1, 2 or 3 and where any carbon atom of(CH₂)_(n) may be substituted by R⁴ and/or R⁵ ;R¹ represents (CH₂)_(q)phenyl, wherein q is zero, 1, 2 or 3, which may be optionallysubstituted in the phenyl ring by 1, 2 or 3 groups selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a), --SO₂ R^(a), --NR^(a)R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) and--CONR^(a) R^(b) ; R² represents aryl selected from phenyl and naphthyl;heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl,tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl orheteroaryl moiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl; R³ represents H or C₁₋₆ alkyl; R⁴ and R⁵ eachindependently represent H, halo, C₁₋₆ alkyl, oxo, CO₂ R^(a) or CONR^(a)R^(b) ; R⁶ represents H or C₁₋₆ alkyl; R⁷ represents H, C₁₋₆ alkyloptionally substituted by a hydroxy group, or (CH₂)_(p) NR⁹ R¹⁰, CO₂R¹⁶, CONR⁹ R¹⁰, (CH₂)_(p) CO₂ R¹⁶, (CH₂)_(p) CONR⁹ R¹⁰, (CH₂)_(p) NR⁹COR¹⁶, (CH₂)_(p) NHSO₂ R¹¹, (CH₂)_(p) OR¹⁶, (CH₂)_(p) OC(O)R⁹, (CH₂)_(p)OC₁₋₄ alkylCOR¹⁷, or phenyl optionally substituted by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b),--COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b) ; R⁸ represents C₁₋₆ alkyl,optionally substituted by oxo, substituted by an optionally substitutedaromatic heterocycle. with the proviso that when R⁶ and R⁷ bothrepresent H, R⁸ represents C₁₋₆ alkyl optionally substituted by oxo,substituted by an optionally substituted aromatic heterocycle selectedfrom pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxadiazolyl,thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzthiophenyl,benzofuranyl and indolyl, or a substituted aromatic heterocycle selectedfrom thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, quinolyl, isoxazolyl and isothiazolyl; R^(a) and R^(b) eachindependently represent H, C₁₋₆ alkyl, trifluoromethyl or phenyloptionally substituted by C₁₋₆ alkyl, halo or trifluoromethyl; R⁹ andR¹⁰ each independently represent H or C₁₋₆ alkyl; R¹¹ represents NR¹⁴R¹⁵ or an optionally substituted aromatic or non-aromatic azacyclic orazabicyclic group; R¹² represents OR^(a), CONR^(a) R^(b) or heteroaryl;R¹³ represents H or C₁₋₆ alkyl; R¹⁴ and R¹⁵ each independently representH, C₁₋₆ alkyl, phenyl optionally substituted by one or more of C₁₋₆alkyl, C₁₋₆ alkoxy, halo or trifluoromethyl, or phenylC₁₋₄ alkyloptionally substituted in the phenyl ring by one or more of C₁₋₆ alkyl,C₁₋₆ alkoxy, halo or trifluoromethyl; R¹⁶ represents C₁₋₆ alkyl; R¹⁷represents C₁₋₆ alkoxy, amino, C₁₋₄ alkylamino or di(C₁₋₄ alkyl)amino;and p is 1 to
 4. 2. A compound as claimed in claim 1 of formula (Ia), ora pharmaceutically acceptable salt thereof: ##STR15## wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁸ and n are as defined in claim 1; andR⁷ representsC₁₋₆ alkyl optionally substituted by a hydroxy group, or (CH₂)_(p) NR⁹R¹⁰, CO₂ R¹⁶, CONR⁹ R¹⁰, (CH₂)_(p) CO₂ R¹⁶, (CH₂)_(p) CONR⁹ R¹⁰,(CH₂)_(p) NR⁹ COR¹⁶, (CH₂)_(p) NHSO₂ R¹¹, (CH₂)_(p) OR¹⁶, (CH₂)_(p)OC(O)R⁹, (CH₂)_(p) OC₁₋₄ alkylCOR¹⁷, or phenyl optionally substituted by1, 2 or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halo, cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a),--SOR^(a), --SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂R^(b), --COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b).
 3. A compound asclaimed in claim 1 of formula (Ib), or a pharmaceutically acceptablesalt thereof: ##STR16## wherein R², R³, R⁴, R⁵, R⁶, R⁸ and n are asdefined in claim 1;R¹⁸ represents C₁₋₆ alkyl optionally substituted by ahydroxy group; and R¹⁹ represents phenyl optionally substituted by 1, 2or 3 groups selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,cyano, nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a),--SOR^(a), --SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂R^(b), --COR^(a), --CO₂ R^(a) and --CONR^(a) R^(b).
 4. A compound asclaimed in claim 1 of formula (Ic), or a pharmaceutically acceptablesalt thereof: ##STR17## wherein R³ and R⁸ are as defined in claim 1;R²⁰and R²¹ independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, chloro, bromo, fluoro, iodo, cyano, nitro, trifluoromethyl,trimethylsilyl, OR^(a), SR^(a), SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), whereR^(a) and R^(b) are as previously defined; R²² is methyl optionallysubstituted by hydroxy; R²³ is H or methyl; and R²⁴ represents phenyl orbenzhydryl wherein any of the phenyl rings of the phenyl or benzhydrylmoieties may optionally be substituted by halo or trifluoromethyl.
 5. Acompound as claimed in claim 1 of formula (Id), or a pharmaceuticallyacceptable salt thereof: ##STR18## wherein R¹, R², R³, R⁴, R⁵, and n areas defined in claim 1; andR⁸ represents C₁₋₆ alkyl, optionallysubstituted by oxo, substituted by an optionally substituted aromaticheterocycle selected from pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl,oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl,benzthiophenyl, benzofuranyl and indolyl, or a substituted aromaticheterocycle selected from thienyl, furyl, pyridyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, quinolyl, isoxazolyl and isothiazolyl.6. A compound as claimed in claim 1 of formula (Ie), or apharmaceutically acceptable salt thereof: ##STR19## wherein R², R³, R⁴,R⁵, R⁸ and n are as defined in claim 1; andR¹⁹ represents phenyloptionally substituted by 1, 2 or 3 groups selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro, trifluoromethyl,trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a), --SO₂ R^(a), --NR^(a)R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --COR^(a), --CO₂ R^(a) and--CONR^(a) R^(b).
 7. A compound as claimed in claim 1 of formula (If),or a pharmaceutically acceptable salt thereof: ##STR20## wherein R³ andR⁸ are as defined in claim 1;R²⁰ and R²¹ independently represent H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, chloro, bromo, fluoro, iodo, cyano,nitro, trifluoromethyl, trimethylsilyl, OR^(a), SR^(a), SOR^(a), SO₂R^(a), NR^(a) R^(b), NR^(a) COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂R^(a) or CONR^(a) R^(b), where R^(a) and R^(b) are as previouslydefined; and R²⁴ represents phenyl or benzhydryl wherein any of thephenyl rings of the phenyl or benzhydryl moieties may optionally besubstituted by halo or trifluoromethyl.
 8. A compound which is cis-3-((3,5-bis(trifluoromethyl))benzylamino)-2-(4-fluorophenyl)piperidine-1-ylmethyl!-2,4-dihydro-1,2,4!-triazol-3-one;or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition comprising a compound as claimed in claim 1in association with a pharmaceutically acceptable carrier or excipient.10. A method for the treatment or prevention of physiological disordersassociated with an excess of tachykinins, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 11. A method according to claim 10 for thetreatment or prevention of pain or inflammation.
 12. A method accordingto claim 10 for the treatment or prevention of migraine.
 13. A methodaccording to claim 10 for the treatment or prevention of emesis.